ELSEVIER Biochimica et Biophysica Acta 1198 (1994) 47-64 BB Biochim~ic~a et Biophysica A~ta Integrin-mediated adhesion and signaling in tumorigenesis Filippo G. Giancotti *, Fabrizio Mainiero Department of Pathology and Kaplan Comprehensive Cancer Center, New York University School of Medicine, 530 FirstAvenue, New York, NY10016, USA (Received 2 February 1994) Contents 1. Introduction .................................................. 47 2. Integrin structure, diversity and regulation ................................. 48 3. Interaction with the cytoskeleton ...................................... 51 4. Integrin signaling and cellular growth .................................... 52 5. Integrin signaling and cellular differentiation ............................... 54 6. The adhesive phenotype of neoplastic cells in culture ........................... 54 7. Changes in integrins in human tumors ................................... 57 8. Integrinsin metastasis ............................................ 59 9. Conclusions and perspectives ........................................ 60 Acknowledgements ................................................. 61 References ...................................................... 61 I. Introduction It is often held that tumor cell malignancy is the direct and only consequence of unrestrained cellular growth, triggered by the activation of oncogenes or inactivation of tumor suppressor genes. Compelling clinical evidence, however, indicates that tumor cells are malignant mainly because of their ability to spread throughout the body and give rise to metastatic foci [1]. Tumor cells present a number of adhesive abnormali- ties which contribute significantly to their ability to * Corresponding author. Fax: + 1 (212) 2638211. 0304-419X/94/$26.00 © 1994 Elsevier Science B.V. All rights reserved SSDI 0304-419X(94)00004-L invade locally and at a distance [2-4]. Experiments of gene transfer have recently linked changes in the ex- pression of integrins [5,6], cadherins [7] and a splice variant of CD44 [8] to tumor invasion. The importance of cell adhesion in tumorigenesis is also highlighted by recent findings in human cancer. These include: the demonstration that DCC, a gene frequently deleted during progression of colon cancer, encodes a cell surface molecule homologous to N-CAM [9]; the obser- vation that the 7:9 translocation of T-cell leukemias disrupts the human homologue of the Drosophila Notch gene, thought to be involved in cell-cell interac- tions [10]; and the realization that the genes disrupted in type 2 neurofibromatosis and familial adenomatous